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Method for synthesizing progesterone

A progesterone and compound technology, applied in the field of progesterone synthesis, can solve the problems of high cost and low yield, and achieve the effect of cheap raw materials, simple reaction steps and mild reaction conditions

Inactive Publication Date: 2020-12-22
HENAN LIHUA PHARMA
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Problems solved by technology

[0003] With the increase of labor cost and environmental protection pressure in China, the price of saponin is more than 800,000 yuan / ton, and the yield of this route is low. Compared with the invention patent application for the preparation method of progesterone CN104262442A, a preparation method of progesterone is disclosed. Specifically, 1,4-androstenedione is used as a raw material, and progesterone is obtained through a three-step reaction of synthesizing ether compounds, synthesizing nitro compounds, and synthesizing progesterone, and the cost is high; compared with CN103848879A, which uses 1,4-androstenedione The invention patent application for the method of preparing progesterone as a raw material discloses a preparation method of progesterone, specifically using 1,4-androstenedione as a raw material, first synthesizing the enol ether of 1,4-androstenedione, Then carry out Wittig reaction to obtain progesterone, compare the invention patent of a synthetic method of progesterone in CN105461776B to provide a kind of synthetic method of progesterone, including steps: 3β-ether-3,5-androstadien-17-one Add ethyl 2-chloropropionate slowly in a solvent with a strong base, and the addition and ring closure reaction will give 3β-ether-3,5-androstadiene-17,20-epoxy-20-methanol Ethyl-20-carboxylate; under the protection of nitrogen or inert gas, in a solvent containing lithium chloride, 3β-ether-3,5-androstadiene-17,20-epoxy-20-methyl -20-Carboxylic acid ethyl ester obtains progesterone through high-temperature decarboxylation, hydrolysis reaction; Contrast the technology of the preparation method of CN104262442A progesterone and use quite expensive (1-methoxyethyl)-triphenylboron tetrafluorophosphine Therefore, it is particularly important to develop a method for the synthesis of progesterone with 4AD or a compound (derivative of 4AD) that is similar to 4AD structure as a raw material that is suitable for industrialized production

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  • Method for synthesizing progesterone

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Embodiment 1

[0021] see figure 1 , the present invention provides a technical scheme: a method for progesterone synthesis, comprising the following steps:

[0022] S1: Synthesis of compound 2, 100g of compound 1 (derivative of 4AD), tetramethylpiperidine oxide in a 2L single-necked bottle, add 3V dichloromethane to dissolve, stir, add sodium bromide, sodium bicarbonate aqueous solution, and then Add 10V sodium hypochlorite solution, stir at 25°C for 16-20h, TLC detects that the reaction of the raw materials is complete, separate the liquid, extract twice with 300mL dichloromethane, combine the organic phase, wash once with water, concentrate to dryness, entrain with methanol twice, then add 10V methanol, concentrated to 3-5V volume, under stirring, 7V water was added dropwise, filtered, and dried at 50°C to obtain 90g of compound 2, HPLC > 98;

[0023] S2: Synthesis of compound 3: under nitrogen protection: add 1-(1-piperidinyl)cyclohexene (self-made) to 2V acetonitrile, heat up to 65-68°...

Embodiment 2

[0027] see figure 1 , the present invention provides a technical scheme: a method for progesterone synthesis, comprising the following steps:

[0028] S1: Synthesis of compound 2, 100g of compound 1 (derivative of 4AD), tetramethylpiperidine oxide in a 2L single-necked bottle, add 3V chloroform to dissolve, stir, add sodium bromide, sodium bicarbonate aqueous solution, and then Add 10V sodium hypochlorite solution, stir at 25°C for 16-20h, TLC detects that the reaction of the raw materials is complete, separate the liquid, extract twice with 300mL chloroform, combine the organic phase, wash once with water, concentrate to dryness, entrain with methanol twice, then add 10V methanol, concentrated to 3-5V volume, under stirring, 7V water was added dropwise, filtered, and dried at 50°C to obtain 90g of compound 2, HPLC > 98;

[0029]S2: Synthesis of compound 3: under nitrogen protection: add 1-(1-piperidinyl)cyclohexene (self-made) to 2V acetonitrile, heat up to 65-68°C to dissol...

Embodiment 3

[0033] see figure 1 , the present invention provides a technical scheme: a method for progesterone synthesis, comprising the following steps:

[0034] S1: Synthesis of compound 2, 100g of compound 1 (derivative of 4AD), tetramethylpiperidine oxide in a 2L single-necked bottle, add 3V dichloromethane to dissolve, stir, add sodium bromide, sodium bicarbonate aqueous solution, and then Add 10V sodium hypochlorite solution, stir at 25°C for 16-20h, TLC detects that the reaction of the raw materials is complete, separate the liquid, extract twice with 300mL dichloromethane, combine the organic phase, wash once with water, concentrate to dryness, entrain with methanol twice, then add 10V methanol, concentrated to 3-5V volume, under stirring, 7V water was added dropwise, filtered, and dried at 50°C to obtain 90g of compound 2, HPLC>98:

[0035] S2: Synthesis of compound 3: under nitrogen protection: add 1-(1-piperidinyl)cyclohexene (self-made) to 2V acetonitrile, heat up to 65-68°C ...

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Abstract

The invention discloses a method for synthesizing progesterone. The method comprises the following steps: S1, performing synthesis of a compound 2: taking a derivative of 4AD as a raw material, takinga derivative of 4AD as a compound 1, taking chloroalkane as a solvent, adding an aqueous solution of tetramethylpiperidine oxide, sodium bromide and sodium bicarbonate, and carrying out oxidation reaction with a sodium hypochlorite solution to obtain the compound 2; S2, synthesizing a compound 3, namely reacting the compound 2 with 1-(1-piperidyl) cyclohexene under the protection of nitrogen by taking acetonitrile as a solvent to obtain a compound 3; S3, performing synthesis of progesterone: taking chloroalkane as a solvent of the compound 3, adding a dimethylformamide solvent for dissolvingcuprous chloride, and carrying out post-treatment to obtain progesterone; and S4, performing purification of progesterone: refining and purifying progesterone by using dichloromethane and sodium hypochlorite. The invention mainly aims at a progesterone synthesis method, and the synthesis route has the advantages of cheap initial raw materials, simple reaction steps, mild reaction conditions, economy, environmental protection, and suitableness for industrial implementation.

Description

technical field [0001] The invention relates to the technical field of progesterone synthesis, in particular to a method for progesterone synthesis. Background technique [0002] The chemical name of progesterone is: 4-pregnene-3,20-dione. This product is a steroidal progesterone drug and an important hormone drug intermediate. It is mainly used for habitual abortion, dysmenorrhea, and menstrual bleeding. Polyuria or bleeding syndrome, amenorrhea, etc. Oral large doses are also used for diseases caused by progesterone deficiency, such as premenstrual syndrome, menstrual disorders caused by cessation of ovulation, benign breast disease, premenopause and menopause, etc. Vaginal administration can replace Oral administration, especially for patients with liver disease, can also be used for benign prostatic hyperplasia and sleep apnea syndrome. The traditional synthesis method is to obtain saponin from turmeric extract through multi-step reactions. [0003] With the increase of...

Claims

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Application Information

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IPC IPC(8): C07J7/00
CPCC07J7/002
Inventor 王海波陈玉真王瑞玲李合兴
Owner HENAN LIHUA PHARMA
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